TNF is involved in pathogenesis of several autoimmune diseases with an inflammatory component and TNF blockers can be very effective for the therapy of rheumatoid arthritis (RA). Over 2 million RA patients have been treated with such drugs worldwide. However, this treatment is not curative since disease usually relapses after interruption of therapy. The standard treatment also interferes with protective functions of TNF against bacterial or other pathogenic infections.
TNF inhibition puts patients at increased risk of opportunistic infections. Warnings have been issued about the risk of infection from two bacterial pathogens, in particular Legionella and Listeria. People taking TNF blockers are at increased risk for developing serious infections that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens. Tuberculosis represents a major risk for patients undergoing anti-TNF treatment. In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab (a known anti-TNF medicament). Before prescribing the drug, physicians should screen patients for latent or chronic TB infection or disease. In some cases, even latent infection screening does not provide suitable or sufficient identification of patients at risk of infections enabled by pan anti-TNF treatments (Jauregui-Amezaga et al., J Crohns Colitis. 2013 Apr. 1; 7(3):208-12).
The anti-TNF monoclonal antibody biologics, such as Infliximab and adalimumab, and the fusion protein etanercept which are all currently approved by the U.S. Food and Drug Administration (FDA) for human use, have warnings which state that patients should be evaluated for latent or chronic TB infection and treatment should be initiated prior to starting therapy with these medications. Additional warnings have been issued that patients on TNF inhibitors are at increased risk of opportunistic fungal infections, such as pulmonary and disseminated histoplasmosis, coccidioidomycosis, and blastomycosis.
Cytokines associated with inflammation and inflammation-related medical disorders, such as TNF-alpha, show both protective and pathological functions, which represents a significant drawback in anti-cytokine therapy. The cell-lineage specific blockade or neutralisation of such cytokines is therefore an important possibility in addressing the different functions of any given cytokine.
The present invention therefore utilises blocking the principal cellular sources of pathogenic TNF in arthritis, and shows how a specific TNF blockade may lead to amelioration of disease symptoms without reduced risks of detrimental side effects due to unwanted neutralisation of protective TNF.
The idea that distinct cellular sources of TNF and its main two molecular forms (secreted and membrane bound) can be distinctly associated with various TNF functions in healthy mice is consistent with a recent study (Tumanov et al. 2010) concerning homeostatic role of TNF in lymphoid tissues, as well as with an earlier work (Grivennikov et al. 2005). It was however unknown in the art that the same is true for the role of TNF in disease: that some cellular sources of TNF may be pathogenic, while others are neutral or protective. The data provided herein demonstrate separate physiological roles in disease for TNF produced by different cellular sub-populations, although a mechanistic explanation of why macrophage TNF is pathogenic in experimental arthritis, while TNF produced by T cells appears protective, is still somewhat unclear.
Using collagen-induced arthritis (CIA) as an animal model for RA, the inventors and others have found that arthritogenic T cells accumulate in large numbers in lymphoid organs of TNF-deficient mice or of wild-type mice treated with TNF blockers, despite the resistance of these mice to disease induction (Notley et al. 2008). Therefore, a pan-TNF blockade may reduce the manifestation of arthritis (possibly by suppressing the infiltration of immune cells into joints), while concomitantly disrupting mechanisms of immune regulation thereby leading to accumulation of pathogenic cells in other body locations. Another possibility is the action of TNF blockers on organized structures of lymphoid tissues, in particular, germinal centers, and related effects on B cell compartment, including B cell memory (Anolik et al. 2008).
Various antibodies directed to TNFα are known in the art. For example WO 2008/003116 A2 discloses a method for engineering an immunoglobulin, in particular for engineering bi-specific antibodies, for an anti-TNF-alpha treatment.
Bi-specific affinity reagents that bind TNFα and an additional marker have been described in the art. WO 2006/063150 A2 discloses methods and reagents for immunotherapy of inflammatory diseases using multi-specific antagonists such as bispecific antibodies that target at least two different markers. Different targets include proinflammatory effectors of the immune system or particular cell types involved in immune responses. The use of an anti-TNF-alpha/anti-CD83 bispecific antibody, which may bind dendritic cells, is disclosed for the treatment of Systemic Lupus Erythematosus (SLE). No details are disclosed regarding a bi-specific affinity reagent directed towards TNFα and a macrophage or neutrophils marker. Furthermore, the concept of differential neutralisation of pathogenic and protective TNFα sub-populations is not disclosed.
Kanakaraj Palanisamy et al (MAbs. 2012 Sep. 1; 4(5): 600-613) disclose a bispecific antibody targeted to TNF-alpha and Ang2 for the treatment of arthritis. According to this publication the combination of anti-TNF-alpha and anti-angiogenic agents may control inflammation more effectively, if angiogenesis initiates chronic inflammation. No details are disclosed regarding a bi-specific affinity reagent directed towards TNFα and a marker for macrophages or neutrophils and the concept of differential neutralisation of pathogenic and protective TNFα sub-populations is not mentioned.